RT Journal Article SR Electronic T1 Pyrexia of unknown origin JF Clinical Medicine JO Clin Med FD Royal College of Physicians SP 170 OP 174 DO 10.7861/clinmedicine.18-2-170 VO 18 IS 2 A1 Cristina Fernandez A1 Nick J Beeching YR 2018 UL http://www.rcpjournals.org/content/18/2/170.abstract AB The syndrome of pyrexia of unknown origin (PUO) was first defined in 1961 but remains a clinical challenge for many physicians. Different subgroups with PUO have been suggested, each requiring different investigative strategies: classical, nosocomial, neutropenic and HIV-related. This could be expanded to include the elderly as a fifth group. The causes are broadly divided into four groups: infective, inflammatory, neoplastic and miscellaneous. Increasing early use of positron emission tomography–computed tomography (PET-CT) and the development of new molecular and serological tests for infection have improved diagnostic capability, but up to 50% of patients still have no cause found despite adequate investigations. Reassuringly, the cohort of undiagnosed patients has a good prognosis. In this article we review the possible aetiologies of PUO and present a systematic clinical approach to investigation and management of patients, recommending potential second-line investigations when the aetiology is unclear.